The applicant's broad objectives are to continue conducting a program of neuroscience research aimed at clarifying mechanisms underlying neuropsychiatric disorders and developing methods for preventing such disorders. His research focus is on excitatory transmitters and related agents that are known to have both neuroexcitatory and neurotoxic properties, the latter stemming from the former and, therefore, being called "excitotoxicity". The applicant's prior research has focused on the role of excitotoxic mechanisms in neuropathological processes; in the coming five years, it will focus both on classical excitotoxicity and on new forms of excitatory transmitter neurotoxicity which the applicant and colleagues have recently discovered. In addition, we will continue to probe the unknown with an aim toward discovering additional neurotoxic mechanisms that may be relevant to human neuropsychiatric disorders. The applicant's research directly addresses neuropathological processes potentially implicated in commonly occurring neuropsychiatric disorders, including schizophrenic and related psychotic processes, Alzheimer's disease, Parkinson's disease, Huntington's disease, perinatal asphyxia and related developmental neuropathological syndromes, stroke and epilepsy-related neuropathology; it also focuses directly on drugs of abuse and mechanisms by which such drugs can cause both neurodegenerative changes in the brain of experimental animals and psychotic reactions in humans. In addition, we are studying the role of excitatory transmitters in cognitive and memory functions and dysfunction. As a new emphasis in the coming 5 years, the applicant will exploit a promising technology which is just becoming available as a result of recent successes in cloning excitatory transmitter receptors, i.e., we will use antibody and nucleotide probes to map and localize various genetically defined excitatory transmitter receptor subunits and study their potential involvement in specific neuropathological processes. To achieve our broad research goals, we will employ a variety of approaches spanning several disciplines, including electron microscopic immunocytochemistry, in situ hybridization histochemistry and receptor autoradiography, neurochemistry, neuropharmacology, neurotoxicology, electrophysiology and behavioral physiology.